Drs. Permutt, Togias and colleagues have previously published evidence that patients with asthma lack a function by which lung inflation protects the airways from smooth muscle-induced obstruction. They propose that this defect is fundamental in asthma and may constitute the mechanism of airway hyperresponsiveness. The goals of this project are to better understand the role of lung inflation in asthma pathophysiology and to identify mechanism(s) which account for the lung inflation effect being poorly functional. With "whole lung" and peripheral airways studies, they will demonstrate a bronchoprotective effect of lung inflation on healthy airways and will compare it to the bronchodilator one. They will further assess whether the loss of these effects is associated with greater asthma morbidity in a cross-sectional evaluation and in a therapeutic trial with inhaled glucocorticosteroids. Using high resolution computerized tomography, they will evaluate the hypotheses that patients with asthma may not be capable of stretching their airways when taking a deep breath, or that the stretch they can achieve does not benefit their airways. By comparing methacholine and allergen challenge in rhinitic-nonasthmatics in the presence and absence of deep inspirations, they will investigate the concept that the allergic reaction interferes with the beneficial effect of lung inflation. This may explain why rhinitics without asthma respond acutely to allergen inhalation similarly to asthmatics. They will first target the sulfidopeptide leukotrienes as potential mediators of such phenomenon because, in the presence of deep inspirations, these substances, when inhaled, poorly differentiate asthmatics from nonasthmatics. They will use a leukotriene antagonist to restore the effect of lung inflation after allergen challenge and will administer leukotrienes to rhinitics-nonasthmatics to mimic the allergen effect. They will also evaluate, in these subjects, whether allergen inhalation challenge has late effects on lung inflation-induced bronchoprotection. By offering an in depth understanding of the way in which airway mechanics lead to the manifestations of asthma, the project should answer many questions behind this disease.